Acne is a commonly occurring skin disorder. It is characterized by an inflammation of the pilosebaceous unit, including the sebaceous gland. Acne lesions can take the form of comedones, papules, pustules, or nodules. Acne lesions typically appear on the face, but also occur on the back, chest and shoulders. Acne lesions are associated with Propionibacterium acnes (P. acnes). Growth of P. acnes is thought to be associated with, if not the cause of, the inflammatory component of acne.
The severity of acne varies widely from individual to individual, and also varies over time for any given individual. Even mild cases of acne can be cosmetically unappealing and at times disfiguring. Occasionally, acne lesions heal but leave permanent scars which are themselves sometimes prominent and permanently disfiguring.
There are a variety of treatments available for acne. Oral antibiotics (e.g. minocycline) may be used to reduce the population of P. acnes. Other oral antibiotics, such as doxycycline, have been used to treat acne when used at concentrations too low to have an antibiotic affect on P. acnes, but high enough to exert an anti-inflammatory action on the acne lesions. Topical retinoids, such as tretinoin, and topical antibiotics, such as clindamycin or azelaic acid, have also been used. In female patients, oral contraceptives have been observed to have an anti-acne effect, and are sometimes prescribed for that purpose. Orally administered isotretinoin is highly effective, but is known to produce a wide array of side effects, including sometimes severe psychiatric effects. Exposure to light, whether in the form of sunlight, or specific wavelengths of light, has also been shown to have a beneficial effect in the treatment of acne.
None of these treatments are compellingly effective, some have undesirable side effects, and all are subject to diminished effectiveness due to poor patient compliance —a common occurrence in the affected age group.
Photodynamic therapy (PDT) is an established therapeutic method for certain disorders. PDT is characterized by the use of (1) a phototherapeutic agent and (2) light. The phototherapeutic agent is applied or provided to the tissue or organ of interest. The light is used to cause a reaction (such as photoexcitation) in either the phototherapeutic agent, or in a metabolite of the phototherapeutic agent, or in a compound produced in response to the presence of the phototherapeutic agent (the activation reaction). This reaction results in a therapeutic effect.
Early phototherapeutic agents included porphyrins such as hematoporphyrin IX, hematoporphyrin derivative, or other such molecules, including Photofrin II.
The pioneering work of Kennedy & Pottier resulted in the discovery of the use of aminolevulinic acid (ALA) as a phototherapeutic agent. ALA is a precursor to a naturally occurring molecule—protoporphyrin IX. Exposing skin to light activates protoporphyrin IX in the skin. That is, the light excites or causes a reaction in the protoporphyrin IX molecule that results in the formation of reactive free radicals. Naturally occurring protoporphyrin IX can be activated by exposure to light, but occurs in quantities too small to cause any serious effect in normal tissue. By administering exogenous ALA, cells and tissues can be caused to produce greatly increased amounts of protoporphyrin IX. The resulting high concentrations of protoporphyrin IX can result in the generation of fatal quantifies of free radicals in the target cells/tissue when protoporphyrin IX is activated by exposure to light.
Kennedy & Pottier found that ALA-induced production of protoporphyrin IX made it possible to use PDT in the treatment of several disorders of metabolically active tissues. This technology has been used in the successful commercial product Levulan®, produced by Dusa Pharmaceuticals, and which has been approved by the U.S. FDA for the treatment of actinic keratoses.
Kennedy and his co-workers believed that ALA-based PDT could be used to treat acne, although they did not report any clinical resolution of acne by this method. See, U.S. Pat. No. 5,955,490. Also, they reported that the ability of light to excite protoporphyrin IX in acne lesions disappeared within 24 hours.
Kennedy reported that the ability of light to excite protoporphyrin IX in skin having acne lesions could persist to 24 hours if an occlusive covering was placed over the skin, but found that when this was done the surrounding healthy skin had as much free-radical generating protoporphyrin IX as did the acne lesions. As Kennedy contemporaneously reported, a phototherapeutic agent must have “a high degree of specificity” for the target tissue. Kennedy, J. C. “Phtochemotherapy-Clinical Aspects” NATO ASI Series, Springer-Verlag at p. 462 (1988). Kennedy's observation of the presence of equal amounts of protoporphyrin IX in acne lesions and in surrounding normal tissue is not specific at all.
Other workers in this field persisted in attempts to employ ALA-based PDT in the treatment of acne. See, U.S. Pat. No. 6,897,238 to Anderson. Anderson used ALA based PDT to treat acne in a small group of patients and taught that light must be applied to the skin within 1 to 12 hours after application of ALA to the skin containing acne lesions, preferably about three hours after application of the ALA.
Anderson's use of a 1 to 12 hour, and preferably a 3 hour waiting period between ALA application and exposure to light was consistent with what was by then the generally accepted timeline of ALA metabolism and protoporphyrin IX production. Research by Kennedy & Pottier showed that ALA was metabolized in mouse skin to result in peak protoporphyrin IX concentration in about six hours, with protoporphyrin levels returning to near pretreatment baseline in about 18 hours. Pottier et al, Photochemistry and Photobiology, Vol. 44, No. 5, pp. 679-87 (1986).
These anecdotal reports of the use of ALA-based PDT to treat acne were eventually followed by a full scale clinical trial on a group of patients large enough to provide statistically meaningful comparisons between the effectiveness of ALA-based PDT on one hand, and exposure to light alone on the other. The result of this clinical trial is available at www.clinicaltrials.gov, NCT 00706433. In this study ALA was applied to skin presenting acne lesions 45 minutes before exposure to activating light. This clinical trial determined that the use of ALA-based PDT produced results that were statistically indistinguishable from the use of light alone. That is, the ALA-based PDT had no effect.
An eight week study compared the effectiveness of ALA-based PDT with exposure to light alone as a treatment for acne. This study also compared delays of 15, 60 and 120 minutes between application of ALA and the exposure to photoactivating light. Among patients where the delay was either 15 or 120 minutes, there was no difference in the results obtained using ALA-based PDT or using light alone. For the 60 minute patients, light alone produced slightly better results than treatment with ALA-based PDT.
Thus, ALA-based PDT has not been an effective treatment for acne.
There exists a need to find a more effective way to utilize ALA-based PDT in the treatment of acne.